AE Reporting Guideline Canada 2009 Guidance-directrice Reporting-notification-Eng

8/14/2019 AE Reporting Guideline Canada 2009 Guidance-directrice Reporting-notification-Eng

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Guidance Document for Industry -

Reporting Adverse Reactions to

Marketed Health Products*

* Marketed Health Products covered by this guidance document are listed in Section 1.1 Scope

and exclude preventative immunization vaccines, blood, blood components, cells, tissues and

organs, and medical devices.

Canada Vigilance Program


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Guidance Docum ent for Industry -

Reporting Adverse Reactions to Marketed Health Products

Health Canada is the federal department responsible for helping the people of Canada

maintain and improve their health. We assess the safety of drugs and many consumer products,

help improve the safety of food, and provide information to Canadians to help them makehealthy decisions. We provide health services to First Nations people and to Inuit communities.

We work with the provinces to ensure our health care system serves the needs of Canadians.

Published by authority of the Minister of Health.

The Guidance Document for Industry - Reporting Adverse Reactions to Marketed HealthProducts is available on the Internet at the following address:http://www.hc-sc.gc.ca/dhp-mps/pubs/medeff/index-eng.php

galement disponible en franais sous le titre :Document dorientation l'intention del'industrie - Dclaration des effets indsirables des produits de sant commercialiss.

Her Majesty the Queen in Right of Canada, represented by the Minister of Health, 2009

This publication may be reproduced without permission provided the source is fullyacknowledged.

PDF: Cat.: H164-33/2009E-PDFISBN: 978-1-100-12682-1


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Reporting Adverse Reactions to Marketed Health Products i

Foreword

Guidance documents are meant to provide assistance to industry and health care professionals onhow to comply with governing statutes and regulations. Guidance documents also provideassistance to staff on how Health Canada mandates and objectives should be implemented in amanner that is fair, consistent and effective.

Guidance documents are administrative instruments not having force of law and, as such, allowfor flexibility in approach. Alternate approaches to the principles and practices described in thisdocument may be acceptable provided they are supported by adequate justification. Alternateapproaches should be discussed in advance with the relevant program area to avoid the possiblefinding that applicable statutory or regulatory requirements have not been met.

As a corollary to the above, it is equally important to note that Health Canada reserves the rightto request information or material, or define conditions not specifically described in thisdocument, in order to allow the Department to adequately assess the safety, efficacy or quality ofa therapeutic product. Health Canada is committed to ensuring that such requests are justifiableand that decisions are clearly documented.


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Reporting Adverse Reactions to Marketed Health Products iii

Table of Contents

1 Introduction ................................................................................................................. 1

1.1 Scope ................................................................................................................. 1

1.2 Definitions .......................................................................................................... 2

1.3 Adverse Reaction Reporting by Market Authorization Holders ........................... 4

1.4 Adverse Reactions .............................................................................................. 4

1.5 Regulations Pertaining to Adverse Reaction Reporting ....................................... 5

1.5.1 Food and Drug Regulations .................................................................... 5

1.5.1.1 Adverse Drug Reaction Reporting (C.01.016, C.01.017) ............. 5

1.5.1.2 New Drugs (C.08.007, C.08.008) ................................................ 6

1.5.2 Natural Health Products Regulations ..................................................... 7

1.5.2.1 Reaction Reporting (Section 24) .................................................. 7

2 General Procedures for Expedited Adverse Reaction Reporting ............................... 9

2.1 Domestic and Foreign Adverse Reaction Reports ............................................... 92.1.1 Domestic Adverse Reaction Reports ..................................................... 10

2.1.2 Foreign Adverse Reaction Reports ........................................................ 10

2.1.2.1 Canadas Access to Medicines Regime ...................................... 10

2.2 Serious Adverse Reaction Reports .................................................................... 11

2.3 Unexpected Adverse Reaction Reports ............................................................. 11

2.4 Other Adverse Reaction Report Types .............................................................. 122.4.1 Unusual Failure in Efficacy .................................................................... 12

2.4.2 Overdose .............................................................................................. 13

2.4.3 Pregnancy Exposure ............................................................................. 13

2.4.4 Discontinued Products .......................................................................... 13


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iv

3 Good Case Management Practices ............................................................................ 15

3.1 Minimum Criteria for an Adverse Reaction Report ........................................... 15

3.2 Assessing Patient and Reporter Identifiability .................................................... 15

3.3 The Role of Narratives ..................................................................................... 16

3.4 Follow-up Information ...................................................................................... 16

3.5 Evaluation and Coding of Adverse Reaction Reports ........................................ 18

3.6 Contractual Agreements ................................................................................... 19

3.7 Records to be Held for Auditing (C.01.017) ..................................................... 19

3.8 Key Data Elements .......................................................................................... 19

4 Adverse Reaction Reports by Source ........................................................................ 23

4.1 Unsolicited Reports .......................................................................................... 23

4.1.1 Consumer Reports ................................................................................ 23

4.1.2 Reports to the Canada Vigilance Regional Offices ................................. 23

4.1.3 Scientific Literature Reports .................................................................. 24

4.1.4 Stimulated Reports ............................................................................... 24

4.1.5 Reports via the Internet ......................................................................... 25

4.1.6 Other Unsolicited Reports ..................................................................... 25

4.2 Solicited Reports .............................................................................................. 25

4.2.1 Patient Support and Disease Management Programs ............................. 26

4.2.2 Reports from Studies ............................................................................ 264.2.2.1 Market Authorization Holder Sponsored Studies ....................... 27

4.2.2.2 Non-Market Authorization Holder Sponsored Studies ............... 27

4.2.2.3 Post-Study Adverse Reactions ................................................... 28

4.2.3 Blinded Study Reports .......................................................................... 28


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Reporting Adverse Reactions to Marketed Health Products v

4.3 Regulatory Authority Sources ........................................................................... 28

5 Summary Reports ...................................................................................................... 31

5.1 Summary Report Format .................................................................................. 31

5.2 Line-listing(s) and Summary Tabulations .......................................................... 33

5.2.1 Presentation of the Line Listing ............................................................. 34

5.2.2 Summary Tabulations ............................................................................ 35

6 Appendices ................................................................................................................. 37

Appendix 1 Glossary: Definitions and Terminology .................................................. 37

Appendix 2 References ............................................................................................ 45

Appendix 3 Abbreviations ........................................................................................ 47

Appendix 4 Contact Information .............................................................................. 49

Appendix 5 Adverse Reaction Reporting Programs .................................................. 51

Appendix 6 World Health Organization Causality Algorithm .................................... 53

Appendix 7 Summary of Expedited Post-Market Adverse Reaction ReportingRequirements to the Marketed Health Products Directorate .................. 55


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vi


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Reporting Adverse Reactions to Marketed Health Products 1

1 Introduction

1.1 Scope

This guidance document provides market authorization holders (MAHs) with assistance on howto comply with theFood and Drugs Act, theFood and Drug Regulations, and theNatural HealthProducts Regulations with respect to reporting adverse reactions (ARs) to marketed healthproducts. ARs for marketed health products within the scope of this guidance document are tobe reported to the Canada Vigilance AR Monitoring Program of the Marketed Health ProductsDirectorate (MHPD) of Health Canada. This guidance document covers the collection of ARreports by the MHPD for the following marketed health products:

1. pharmaceutical drugs (which includes prescription and non-prescription

pharmaceutical drugs);

2. biologics as set out in Schedule D to theFood and Drugs Act(which includebiotechnology products, therapeutic and diagnostic vaccines and fractionatedblood products), but excluding blood and blood components and preventativeimmunization vaccines;

3. radiopharmaceutical drugs set out in Schedule C to theFood and Drugs Act; and

4. natural health products as defined in Section 1 of theNatural Health ProductsRegulations.

In addition to the requirement for MAHs to submit AR reports in accordance with theFood andDrugs Act, theFood and Drug Regulations and theNatural Health Products Regulations(collectively these two sets of regulations are referred to hereafter as the Regulations), HealthCanada has powers to request additional information on ARs as set out in the Regulations1, 2, 3.

Note that drugs and natural health products authorized for clinical trials involving humansubjects pursuant to Part C, Division 5 of theFood and Drug Regulations4 and Part 4 of theNatural Health Products Regulations, respectively, are not within the scope of this guidancedocument.

Other parts of Health Canada and certain Health Canada partners collect AR reports on otherproducts. Appendix 5 provides further details on these other reporting programs.


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1.2 Definitions

Definitions for a number of terms used in this document are set out below. A complete Glossary

is included in Appendix 1.

Adverse reaction (AR) for the purpose of this guidance document means a noxious andunintended response to a marketed health product covered by this document and includesadverse drug reaction as defined in theFood and Drug Regulations5 and adverse reaction asdefined in theNatural Health Products Regulations6.

Adverse drug reaction as defined in theFood and Drug Regulations5 means a noxiousand unintended response to a drug, which occurs at doses normally used or tested for thediagnosis, treatment or prevention of a disease or the modification of an organic function.

Adverse reaction as defined in theNatural Health Products Regulations6 means anoxious and unintended response to a natural health product that occurs at any dose usedor tested for the diagnosis, treatment or prevention of a disease or for modifying anorganic function.

Serious adverse reaction for the purpose of this guidance document means a noxious andunintended response to a marketed health product covered by this document that occurs at anydose and that requires in-patient hospitalization or prolongation of existing hospitalization, thatcauses congenital malformation, results in persistent or significant disability or incapacity, islife-threatening or results in death and includes serious adverse drug reaction as defined in theFood and Drug Regulations5 and serious adverse reaction as defined in theNatural HealthProducts Regulations6.

Serious adverse drug reaction as defined in theFood and Drug Regulations5 means anoxious and unintended response to a drug that occurs at any dose and that requiresin-patient hospitalization or prolongation of existing hospitalization, causes congenitalmalformation, results in persistent or significant disability or incapacity, islife-threatening or results in death.

Serious adverse reaction as defined in theNatural Health Products Regulations6 means

a noxious and unintended response to a natural health product that occurs at any dose andthat requires in-patient hospitalization or a prolongation of existing hospitalization, thatcauses congenital malformation, that results in persistent or significant disability orincapacity, that is life threatening or that results in death.


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Health product for the purpose of this guidance document includes drugs and natural healthproducts. Drugs include both prescription and nonprescription pharmaceuticals; biotechnology

products and biologically-derived products such as vaccines, serums, and blood derivedproducts; disinfectants; and radiopharmaceuticals. Note however, as set out in Section 1.1, thatonly some of these health products fall within the scope of the AR reporting covered by thisguidance document.

Drug as defined in theFood and Drugs Act6 includes any substance or mixture ofsubstances manufactured, sold or represented for use in:

a. the diagnosis, treatment, mitigation or prevention of a disease, disorder orabnormal physical state, or its symptoms, in human beings or animals,

b. restoring, correcting or modifying organic functions in human beings or animals,or

c. disinfection in premises in which food is manufactured, prepared or kept.

Natural health product as defined in theNatural Health Products Regulations6 is asubstance set out in Schedule 1 of theNatural Health Products Regulations or acombination of substances in which all the medicinal ingredients are substances set out inSchedule 1 of theNatural Health Products Regulations, a homeopathic medicine or atraditional medicine, that is manufactured, sold or represented for use in

a. the diagnosis, treatment, mitigation or prevention of a disease, disorder orabnormal physical state or its symptoms in humans;

b. restoring or correcting organic functions in humans; or

c. modifying organic functions in humans, such as modifying those functions in amanner that maintains or promotes health.

However, a natural health product does not include a substance set out in Schedule 2 oftheNatural Health Products Regulations, any combination of substances that includes asubstance set out in Schedule 2 of theNatural Health Products Regulations or a

homeopathic medicine or a traditional medicine that is or includes a substance set out inSchedule 2 of theNatural Health Products Regulations.


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Market authorization holder (MAH) for the purpose of this guidance document means theentity that holds the Notice of Compliance, the Drug Identification Number (DIN), the Natural

Product Number (NPN), the Homeopathic Medicine Number (DIN-HM), or the product licence.Qualified Health Care Professional for the purpose of this guidance document means aperson who is a member in good standing of a professional medical, nursing, pharmacists orother health care practitioner association and entitled to provide health care under the laws of thejurisdiction in which the person is located, and other individuals retained by the MAH who havethe appropriate health care education and therapeutic expertise.

1.3 Adverse Reaction Reporting by Market Authorization Holders

Every MAH is required to report ARs known to them involving their marketed health products

in accordance with the requirements of theFood and Drugs Actandthe Regulations1, 2, 3

. Thesuccess of Health Canadas AR reporting system depends on the quality, completeness, andaccuracy of the information submitted. Reporting of ARs and the monitoring thereof remain aviable means of identifying previously unrecognized, rare or serious ARs . This may result inchanging product safety information, facilitating decisions on regulatory actions such aswithdrawal of a product from the Canadian market, contributing to international data regardingrisks and effectiveness of health products, and imparting health product safety knowledge thatbenefits all Canadians.

In facilitating reporting of ARs by MAHs, Health Canada has harmonized to the greatest extent

possible the recommendations in the International Conference on Harmonisation of TechnicalRequirements for Registration of Pharmaceuticals for Human Use (ICH) guidance documents:Clinical Safety Data Management: Definitions and Standards for Expedited Reporting9(ICHE2A), Clinical Safety Data Management: Periodic Safety Update Reports for Marketed Drugs10

(ICH E2C(R1)), andPost-approval Safety Data Management: Definitions and Standards forExpedited Reporting11 (ICH E2D),Pharmacovigilance Planning12(ICH E2E), and the Report ofthe Council for International Organizations of Medical Sciences (CIOMS) V Working Group:Current Challenges in Pharmacovigilance: Pragmatic Approaches12.

1.4 Adverse Reactions

This guidance document applies to adverse reactions rather than adverse events (AEs). ARs tomarketed health products covered by this document may be generated from unsolicited andsolicited reports.


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An AR, in contrast to an AE, is characterized by the fact that a causal relationship between thedrug and the occurrence is suspected. The definition of adverse reaction (see Section 1.2)

implies that there is a suspected relatedness to the administered health product. Healthprofessionals and consumers report adverse reactions because of their suspicion of therelatedness of an adverse event to a health product. The description of experiences in thesereports should therefore be considered adverse reactions. Reportable ARs also include thosesuspected of being the result of drug interactions (e.g., drug-drug interactions, drug-naturalhealth product interactions, drug-food interactions).

An adverse event, as defined in ICH E2D11, means any untoward medical occurrence in a patientadministered a medicinal product and which does not necessarily have to have a causalrelationship with this treatment. An AE can therefore be any unfavourable and unintended sign

(for example, an abnormal laboratory finding), symptom, or disease temporally associated withthe use of a medicinal product, whether or not considered related to this medicinal product.

1.5 Regulations Pertaining to Adverse Reaction Reporting

The sections of the applicable regulations that set out the AR reporting requirements are listedbelow.

1.5.1 Food and Drug Regulations

1.5.1.1 Adverse Drug Reaction Reporting (C.01.016, C.01.017)

C.01.016.

(1) No manufacturer shall sell a drug unless the manufacturer, with respect to anyadverse drug reaction or any serious adverse drug reaction known to themanufacturer that occurs after this section comes into force, furnishes to theDirector

(a) a report of all information in respect of any serious adverse drug reactionthat has occurred in Canada with respect to the drug, within 15 days afterreceiving the information; and

(b) a report of all information in respect of any serious unexpected adversedrug reaction that has occurred outside Canada with respect to the drug,within 15 days after receiving the information.


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(2) The manufacturer shall, on an annual basis and whenever requested to do so bythe Director, conduct a concise, critical analysis of the adverse drug reactions and

serious adverse drug reactions to a drug referred to in subsection (1) and prepare asummary report in respect of the reports received during the previous twelvemonths or received during such period of time as the Director may specify.

(3) Where, after reviewing any report furnished pursuant to subsection (1) and anyavailable safety data relating to the drug, the Director considers that the drug maynot be safe when used under the recommended conditions of use, the Directormay, for the purpose of assessing the safety of the drug, request in writing, thatthe manufacturer submit

(a) case reports of all adverse drug reactions and serious adverse drug

reactions to that drug that are known to the manufacturer; and

(b) a summary report prepared pursuant to subsection (2).

(4) The manufacturer shall submit the case reports and summary report referred to insubsection (3) within 30 days after receiving the request from the Director.

C.01.017.

The manufacturer shall maintain records of the reports and case reports referred to insection C.01.016 for auditing purposes.

1.5.1.2 New Drugs (C.08.007, C.08.008)

C.08.007.

Where a manufacturer has received a notice of compliance issued in respect of a newdrug submission or abbreviated new drug submission or a supplement to eithersubmission, the manufacturer shall establish and maintain records, in a manner thatenables an audit to be made, respecting...

(h) any unusual failure in efficacy of that new drug.

C.08.008.

No manufacturer shall sell a new drug unless the manufacturer has, with respect to all themanufacturer's previous sales of that new drug, furnished to the Minister...


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(c) within 15 days after the receipt by the manufacturer of information referred to inparagraphs C.08.007(g) and (h), a report on the information received.

1.5.2 Natural Health Products Regulations

1.5.2.1 Reaction Reporting (Section 24)

Section 24.

24.(1) A licensee shall provide the Minister with

(a) a case report for each serious adverse reaction to the natural health productthat occurs inside Canada, within 15 days after the day on which thelicensee becomes aware of the reaction; and

(b) a case report for each serious unexpected adverse reaction to the naturalhealth product that occurs inside or outside Canada, within 15 days afterthe day on which the licensee becomes aware of the reaction.

(2) A licensee who sells a natural health product shall annually prepare and maintaina summary report that contains a concise and critical analysis of

(a) all adverse reactions to the natural health product that have occurredinside Canada; and

(b) all reactions for which a case report is required to be provided undersubsection (1), that have occurred

(i) during the previous 12 months, and

(ii) at a dose used or tested for the diagnosis, treatment or preventionof a disease or for modifying organic functions in humans.

(3) If after reviewing a case report provided under subsection (1) or after reviewingany other safety data relating to the natural health product, the Minister hasreasonable grounds to believe that the natural health product may no longer be

safe when used under the recommended conditions of use, the Minister mayrequest that, within 30 days after the day on which the request is received, thelicensee


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(a) provide to the Minister a copy of any summary report prepared undersubsection (2); or

(b) prepare and provide to the Minister an interim summary report containinga concise and critical analysis of

(i) all adverse reactions to the natural health product that haveoccurred inside Canada, and

(ii) all reactions for which a case report is required to be providedunder subsection (1), that have occurred

(A) since the date of the most recent summary report preparedunder subsection (2), and

(B) at a dose used or tested for the diagnosis, treatment orprevention of a disease or for modifying organic functionsin humans.


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2 General Procedures for Expedited Adverse Reaction Reporting

Every MAH should put into place written procedures for the receipt, evaluation, and reporting of

ARs.

ARs to the marketed health products covered by this guidance document are to be reported to theMHPD. The preferred reporting format for AR reporting by MAHs is as follows:

The Council for International Organizations of Medical Sciences (CIOMS) IForm

Health Canada also provides a voluntary reporting form by which consumers and healthprofessionals can report ARs:

Canada Vigilance Reporting Form HC/SC 4016

2.1 Domestic and Foreign Adverse Reaction Reports

For drugs, MAHs must submit domestic and foreign AR reports to the MHPD pursuant to PartC, Division 1 (C.01.016) and for new drugs must submit reports of unusual failure in efficacypursuant to Part C, Division 8 (C.08.007, C.08.008) of theFood and Drug Regulations oncetheir drugs are sold on the market in Canada. These reporting obligations (see sections 2.1.1and 2.1.2) for MAHs commence when the MAH sells a drug, which can occur for example whena MAH offers a drug for sale, exposes a drug for sale or has a drug in its possession for sale and

distribution.For natural health products, MAHs must submit domestic and foreign AR reports to the MHPDas set out in Section 24 of theNatural Health Products Regulations once their health product islicensed to be marketed in Canada.

To facilitate the processing of AR reports, the MAH should indicate if the report is domestic orforeign by clearly noting the country where the reaction occurred on the reporting form.

The regulatory reporting time clock is considered to start on the day when the MAH (the entitythat holds the DIN, NPN, or DIN-HM (see Section 1.2)) first has all of the information that

satisfies the minimum criteria for an AR report (see Section 3.1). This date should be consideredday 0. MAHs are expected to seek ways to accelerate communications between themselves andtheir affiliates to promote compliance with MAH adverse reaction reporting responsibilities.
http://www.cioms.ch/http://www.cioms.ch/http://www.hc-sc.gc.ca/dhp-mps/medeff/report-declaration/ar-ei_form-eng.phphttp://www.hc-sc.gc.ca/dhp-mps/medeff/report-declaration/ar-ei_form-eng.phphttp://www.cioms.ch/http://www.cioms.ch/


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2.1.1 Domestic Adverse Reaction Reports

AR reports concerning reactions occurring in Canada to a product that is marketed in

Canada are considered domestic AR reports.

In order to report in accordance with the Regulations1, 2, 3, it is sufficient that each MAHreport to the MHPD in an expedited fashion (within 15 calendar days of receiving therelevant information) the following domestic reports:

serious ARs

unusual failure in efficacy reports for new drugs.

2.1.2 Foreign Adverse Reaction Reports

AR reports concerning reactions occurring outside Canada to a product that is marketedin Canada are considered foreign reports.

In order to report in accordance with the Regulations1, 2, 3, it is sufficient that each MAHreport to the MHPD in an expedited fashion (within 15 calendar days of receiving therelevant information) the following foreign reports:

serious unexpected ARs.

All foreign serious unexpected AR reports involving foreign products with the same

combination of active ingredients irrespective of variations in the formulation, dosageform, strength, route of administration, or indication, that is also marketed in Canadamust be reported to the MHPD in accordance with the Regulations1,2,3 (e.g., a MAH thatsells a marketed health product in Canada with active ingredients X, Y, and Z, mustreport all foreign serious unexpected AR reports involving a foreign product with activeingredients X, Y, Z).

2.1.2.1 Canadas Access to Medicines Regime

In response to public health problems afflicting many developing and least-

developed countries, Canada passed on May 14, 2004 Bill C-9,An Act to amendthe Patent Act and the Food and Drugs Act(The Jean Chrtien Pledge to Africa).The Act, which came into force on May 14, 2005, creates a legislative frameworkthat enables manufacturers to obtain an authorization (i.e., compulsory licence)allowing them to make, construct and use a patented invention solely for the


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purpose of exporting a pharmaceutical product to eligible importing countries.The provisions of the Act are now incorporated in thePatent Actand theFood

and Drugs Act, following their amendment after the coming into force of the Act.Compulsory licence holders are subject to the requirements for reporting foreignadverse reactions to health products sold under Canadas Access to MedicinesRegime (CAMR). Compulsory licence holders submitting these reports to theMHPD are requested to specify the following on the cover sheet: ForeignAdverse Reaction, Canadas Access to Medicines Regime.

2.2 Serious Adverse Reaction Reports

A serious adverse reaction is defined in the Regulations5, 6 as a noxious and unintended response

to a drug or natural health product that occurs at any dose and that requires in-patienthospitalization or prolongation of existing hospitalization, causes congenital malformation,results in persistent or significant disability or incapacity, is life-threatening or results in death.

Medical and scientific judgement by a qualified health care professional should be exercised indeciding whether expedited report ing is appropriate in other situations, such as importantmedical events that may not be immediately life-threatening or result in death or hospitalizationbut may jeopardize the patient or may require intervention to prevent one of the other outcomeslisted in the definition from the Regulations5, 6. Health Canada asks that these cases be reportedon an expedited basis as well. Examples of such events are intensive treatment in an emergency

room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result inhospitalization, or development of drug dependency or drug abuse.

2.3 Unexpected Adverse Reaction Reports

An AR is considered unexpected when its nature (i.e., specificity or outcome), severity orfrequency is either not identified, or is not consistent with the term or description used in theproduct labelling. In cases where the MAH is uncertain whether an AR is expected orunexpected, the AR should be treated as unexpected.

For both domestic and foreign reports, expectedness is determined from relevant Canadian

labelling such as the product monograph, labelling standards, information approved for marketauthorization, or the product label.


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For cases that involve a fatal outcome, AR reports should be considered unexpected unless theproduct labelling specifically states that the AR may be associated with a fatal outcome.

Class ARs should not automatically be considered expected for the subject health product. ClassARs should be considered expected only if described as specifically occurring with the productin the product labelling as illustrated in the following examples:

As with other health products of this class, the following undesirable effectoccurs with Product X.

Health products of this class, including Product X, can cause...

If the AR has not been documented with Product X, statements such as the following are likelyto appear in the product labelling:

Other health products of this class are reported to cause...

Health products of this class are reported to cause..., but no reports have beenreceived to date with Product X.

In these situations, the AR should not be considered as expected for Product X.

2.4 Other Adverse Reaction Report Types

2.4.1 Unusual Failure in Efficacy

The MAH may use the CIOMS I form to report an unusual failure in efficacy of a newdrug in accordance with Part C, Division 8 of theFood and Drug Regulations2. ForNewDrugs marketed in Canada, domestic reports of unusual failure in efficacy must bereported to the MHPD within 15 calendar days of the receipt of information by the MAH.Inquiries regarding new drug status for health products marketed in Canada should bereferred to the appropriate Directorate (i.e., Biologics and Genetic Therapies Directorateor Therapeutic Products Directorate).

The underlying principle is that if a health product fails to produce the expected intended

effect, there may be an adverse outcome for the patient, including an exacerbation of thecondition for which the health product is being used. Clinical judgement should beexercised by a qualified health care professional from the MAH to determine if theproblem reported is related to the product itself, rather than one of treatment selection ordisease progression since health products cannot be expected to be effective in 100% of


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the patients. One example of unusual failure in efficacy is a previously well-stabilizedcondition that deteriorates when the patient changes to a different brand or receives a

new prescription. Another example of a case that should be reported on an expeditedbasis is a life-threatening infection where the failure in efficacy seems to be due to thedevelopment of a newly resistant strain of bacterium previously regarded as susceptible.

In cases where the MAH is uncertain whether an AR should be considered as a report ofunusual failure in efficacy, the AR should be treated as such and submitted to the MHPDaccordingly. For consumer reports, emphasis should be placed on the quality of thereport and not on its source.

2.4.2 Overdose

Reports of overdose with no associated adverse outcomes should not be reported as ARs.Cases of overdose associated with serious ARs are subject to expedited reporting. Theyshould be routinely followed up to ensure that the information is as complete as possiblewith regard to symptoms, treatment, and outcome. The MAH should collect anyavailable information on overdose related to its products.

2.4.3 Pregnancy Exposure

MAHs are expected to follow up all pregnancy reports from health care professionals andconsumers where the embryo/foetus could have been exposed to one of its healthproducts. For consumer reports, it is appropriate to seek permission to only follow-upwith the health care professional. The MAH must apply all principles outlined in thisguidance document and the Regulations1, 2, 3 pertaining to reporting requirements,including determination of seriousness and minimal criteria for submitting an AR report.When an active substance, or one of its metabolites, has a long half-life, this should betaken into account when considering whether a foetus could have been exposed (e.g., ifhealth products taken before the gestational period should be considered).

2.4.4 Discontinued Products

In accordance with the Regulations1, 2, 3, the MAH must report any AR information

received prior to the discontinuation of sale in Canada but is not obliged to report anynew cases of adverse reactions received following the products discontinuation unlessotherwise requested by Health Canada. If a serious AR was known to the MAH beforethe discontinuation of sale, they must still report as per the expedited reportingrequirements even if the end of the 15-day reporting timeframe as required by the


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Regulations1, 2, 3 is after the date on which sales were discontinued. Follow-upinformation for cases known to the MAH prior to the discontinuation of sale should be

reported to the MHPD in accordance with the Regulations, and should be sought as partof the follow-up practices described under Section 3.4.

When expired and unexpired lots of a discontinued product are available in pharmacies,the MAH is still under obligation to report ARs to the MHPD when required by HealthCanada. Even though it is conceivable that the MAH only becomes aware of ARs afterthe discontinuation and after all lots have expired, they must still report these reactions tothe MHPD on request.


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3 Good Case Management Practices

3.1 Minimum Criteria for an Adverse Reaction Report

Complete information for the final description and evaluation of an AR report may not beavailable within the time frame required for reporting. Nevertheless, for regulatory purposes,AR reports must be submitted within the prescribed time, as long as the following minimumcriteria are met:

(a) An identifiable reporter (source)

(b) An identifiable patient

(c) A suspect product

(d) An adverse reaction.

Ideally, more comprehensive information would be available on all cases from the outset, but inpractice MAHs will often have to follow up after initially submitting the report to seek additionalinformation. Follow-up AR reports should be clearly labelled as such. The MAH is expected toexercise due diligence to collect any key data elements (see Section 3.8) that are lacking at thetime of initially submitting the report.

It is important that at the time of the original report, sufficient details about the patient andreporter be collected and retained to enable follow-up in accordance with the collection, use and

disclosure provisions of thePersonal Information Protection and Electronic Documents Actorequivalent provincial privacy legislation.

3.2 Assessing Patient and Reporter Identifiability

Patient and reporter identifiability is important to avoid case duplication, and facilitate follow-upof appropriate cases. The term identifiable in this context refers to the verification of theexistence of a patient and a reporter. AR cases without specific identifiers meet the first tworeporting criteria outlined in section 3.1. However, follow-up information should be activelysought and submitted as it becomes available. All parties submitting case information or

approached for case information should be identifiable: not only the initial reporter (the initialcontact for the case), but also others supplying information. In addition, in the event of second-hand reports, every reasonable effort should be made to verify the existence of an identifiablepatient and reporter.


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One or more of the following should automatically qualify a patient as identifiable: age or agecategory (e.g., adolescent, adult, elderly), gender, patient identification number, or reference to

a patient. In the absence of qualifying descriptors (e.g., age, gender), a report referring to anumber of patients should not be regarded as a case until the minimum four criteria for casereporting are met. For example, Two patients experienced... or a few patients experiencedshould be followed up for patient-identifiable information before reporting to the MHPD. Theminimum criteria must be met for each reported patient.

3.3 The Role of Narratives

The objective of the narrative is to summarize all relevant clinical and related information,including patient characteristics, therapy dates, medical history, clinical course of the event(s),diagnosis, and AR(s) including the outcome, laboratory evidence (including normal ranges), and

any other information that supports or refutes an AR (e.g., rechallenge information). Thenarrative should serve as a comprehensive, stand-alone medical story.

Abbreviations and acronyms should be avoided, with the possible exception of laboratoryparameters and units. Key information from supplementary records including summarizedrelevant autopsy or post-mortem findings should be included in the report, and their availabilityshould be mentioned in the narrative and supplied on request . Clinical judgement should beexercised by a qualified health care professional from the MAH to determine what informationshould be submitted. Personal identifiers should only be submitted in accordance with thecollection, use and disclosure provisions of thePersonal Information Protection and Electronic

Documents Actor equivalent provincial privacy legislation.

Information (e.g., ARs, indication, and medical conditions) in the narrative should be accuratelyreflected in appropriate data fields of the reporting form.

3.4 Follow-up Information

Follow-up information should be actively sought and submitted as it becomes available forappropriate amendment to the database and files in the MHPD. Follow-up AR reports should beclearly labelled as such. Specific reference should be made to the initial report by including theMAH number specific to the report either in the follow-up report or on the fax cover sheet.

Follow-up information should be clearly identified, and should be updated in the narrativesequentially by the date it was received by the MAH. Corresponding data fields should beupdated on the reporting form.


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When additional medically relevant information is received for a previously reported case, thereporting time clock (see Section 2.1) is considered to begin again for submission of the follow-

up report. Follow-up information received by the MAH for serious domestic ARs and seriousunexpected foreign ARs must be reported to the MHPD within 15 calendar days. In addition, acase initially classified as a non-expedited report, would qualify for expedited reporting uponreceipt of follow-up information that indicates the case should be re-classified (e.g., from non-serious to serious).

In any scheme to optimize the value of follow-up, the first consideration should be prioritizationof case reports by importance. The priority for follow-up should be as follows: cases which are(1) serious and unexpected, (2) serious and expected, and (3) non-serious and unexpected.Although non-serious and unexpected cases are not expedited, MAHs are encouraged to pursue

follow-up information on these reports. In addition, cases of special interest also deserve extraattention as high priority (e.g., ARs under enhanced or active surveillance at the request ofHealth Canada), as well as any cases that might lead to a labelling change decision.

Follow-up information should be obtained, via a telephone call and/or site visit and/or a writtenrequest. The MAH should ask specific questions it would like to have answered. Follow-upmethods should be tailored towards optimizing the collection of missing information. Ifappropriate, written confirmation of details given verbally should be obtained. All attempts toobtain follow-up information (whether or not successful) should be documented as part of thecase file, particularly on the priority cases. The number of follow-up attempts along with thedate and time of each is recommended to reflect sufficient diligence.

To facilitate the capture of clinically relevant and complete information, use of a targetedquestionnaire/specific form is encouraged, preferably at the time of the initial report. Ideally,qualified health care professionals should be involved in the collection and the direct follow-upof reported cases. For serious ARs, it is important to continue follow-up and report newinformation until the outcome has been established or the condition is stabilized. The amount oftime devoted to follow up such cases is a matter of the qualified health care professionalsjudgement.


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3.5 Evaluation and Coding of Adverse Reaction Reports

The purpose of careful medical review by qualified health care professionals is to ensure correct

interpretation of medical information. Preferably, information about the case should be collectedfrom the healthcare professionals who are directly involved in the patients care. Regardless ofthe source of an AR report, the MAH should carefully review the report for the quality andcompleteness of the medical information. The review should include, but is not limited to, thefollowing considerations:

Has a diagnosis been assigned?

Have the relevant diagnostic procedures been performed?

Were alternative causes of the reaction(s) considered?

What additional information is needed?

The Medical Dictionary for Regulatory Activities (MedDRA), an ICH initiative (ICH M1), is aninternationally accepted, clinically validated medical terminology developed to share regulatoryinformation about medical products used by humans. MedDRA provides a set of terms whichconsistently categorizes medical information and is meant to standardize the terminologythrough which medical regulatory information is classified, stored, retrieved, presented andcommunicated. In order to avoid loss or distortion of communicated information, it isrecommended that MedDRA be used as a standard for the coding of AR reports.

Every effort should be made to use AR terms consistently and in accordance with recommendedstandards for diagnosis. The report should include the verbatim term as used by the reporter, oran accurate translation of it. Any MAH personnel receiving reports should provide an unbiasedand unfiltered report of the information from the reporter. While the report recipient isencouraged to actively query the reporter to elicit the most complete account possible, inferencesand imputations should be avoided in report submission. However, clearly identified evaluationsby the MAH are considered appropriate.

When a case is reported by a consumer, his/her description of the event should be retained,

although confirmatory or additional information from any relevant qualified health careprofessionals should also be sought and included as part of the follow-up practices describedunder Section 3.4.


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3.6 Contractual Agreements

The marketing of many health products increasingly takes place through contractual agreements

between two or more companies, which may market the same product in the same or differentcountries or regions. Arrangements vary considerably with respect to inter-MAHcommunication and regulatory responsibilities. Therefore, it is very important that explicitlicensing or contractual agreements specify the processes by which an exchange of safetyinformation, including timelines and regulatory reporting responsibilities, are taking place.Safety personnel should be involved in the development of any agreements from the beginning.Processes should be in place to avoid duplicate reporting to the regulatory authority (e.g.,assigning the responsibility to one MAH for literature screening).

Whatever the nature of the arrangement, the MAH is ultimately responsible for regulatory

reporting. Therefore, every effort must be made between the contracting partners to minimizethe data exchange period so as to promote compliance with MAH reporting responsibilities.

3.7 Records to be Held for Auditing (C.01.017)

TheFood and Drug Regulations14 require that records of the annual summary reports and ARcase reports be maintained to permit audit or submission on request. A minimum 25 yearretention period is recommended from the date the record was created. It is also recommendedthat these records be easily accessible within 72 hours.

Information regarding the Post-Market Reporting Compliance inspection program conducted bythe Health Products and Food Branch Inspectorate is available through the following documents:Inspection Strategy for Post-Market Surveillance (POL-0041), andRisk Classification of Post-Market Reporting Compliance Observations (GUI-0063).

3.8 Key Data Elements

The following is a list of suggested items that enhance the quality of an AR report. Attemptsshould be made to obtain information on as many listed items as are pertinent to the case.

1. Patient Details

Unique identifier (to readily locate the case for follow-up purposes; do notuse the patients name or initials)

Gender


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Age, age category (e.g., adolescent, adult, elderly)

Height and weight

Pre-existing conditions

Medical history

Relevant family history

2. Suspected Health Product(s)

Brand name as reported

Common Name, e.g., International Nonproprietary Name (INN)

For natural health products, it is important to include the Latin binomial,author reference, family, type of extract (e.g., aqueous versus alcoholic,including percent of solvent), part of the plant used (in the case of a herbalproduct), ingredients and quantity of each (for combination products - thesuspected ingredient), and potency (for homeopathic products)

Batch/lot number

Indication(s) for which suspect health product was prescribed or tested

Dosage form and strength

Daily dose (specify units, e.g., mg, ml, mg/kg) and regimen

Route of administration

Starting date and time

Stopping date and time, and duration of treatment

3. Other Treatment(s)

The same information as in item 2 should be provided for the following:


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Concomitant health products (including non-prescription, over-the-countermedicinal products, natural health products, dietary supplements,

complementary and alternative therapies, etc.) Relevant medical devices

4. Details (all available) of Adverse Reaction(s)

Full description of reaction(s), including body site and severity

The criterion (or criteria) for regarding the report as serious if reported assuch

Description of the reported signs and symptoms

Specific diagnosis for the reaction

Onset date (and time) of reaction

Stop date (and time) or duration of reaction

Dechallenge and rechallenge information

Relevant diagnostic test results and laboratory data

Setting (e.g., hospital, out-patient clinic, home, nursing home)

Outcome (recovery and any sequelae)

For a fatal outcome, stated cause of death

Relevant autopsy or post-mortem findings

Relatedness of product to reaction(s)/event(s)

5. Details on Reporter of an Adverse Reaction

Reporter type (consumer, healthcare professional, etc.)

Profession (specialty)


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6. Administrative and Market Authorization Holder Details

Source of report (e.g., clinical trial, literature, spontaneous, regulatory

authority)

Date the event report was first received by MAH

Country in which the reaction occurred

Type (initial or follow-up) and sequence (first, second, etc.) of caseinformation reported to Health Canada

Name and address of MAH

Name, address, electronic mail address, telephone number, and facsimilenumber of contact person of MAH

MAHs identification number for the case (the same number should beused for the initial and follow-up reports on the same case)


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4 Adverse Reaction Reports by Source

4.1 Unsolicited Reports

An unsolicited report is a spontaneous report which is defined by the ICH11 as an unsolicitedcommunication by a health care professional or consumer to a MAH, regulatory authority (i.e.,Health Canada) or other organization that describes one or more ARs in a patient who was givenone or more health products and that is not derived from a study or any organized data collectionscheme.

4.1.1 Consumer Reports

Consumer AR reports should be handled as spontaneous reports irrespective of anysubsequent medical confirmation. Emphasis should be placed on the quality of thereport and not on its source.

If a MAH receives a report from a consumer, it is recommended that the MAH encouragethe patient to report the reaction through his or her health care professional or permissionshould be sought to contact the consumers health care professional. In addition, theMAH should attempt to obtain as much information as possible from the patient.Consumers report adverse reactions because of their suspicion of the relatedness of anadverse event to a health product. The description of the experiences in these reportsshould therefore be considered adverse reactions.

If the minimum reporting criteria are met and the report is considered relevant by aqualified health care professional from the MAH, the case is considered reportable andmust be forwarded to the MHPD in accordance with the Regulations1,2,3. Even if reportsreceived from consumers do not qualify for regulatory reporting, the cases should beretained.

4.1.2 Reports to the Canada Vigilance Regional Offices

If a MAH becomes aware of a report that has been submitted by a practitioner orconsumer to one of the official Canada Vigilance Regional Offices, the MAH must also

submit the report to the MHPD in accordance with the Regulations1,2,3

and should clearlyindicate that the report was also sent to a Canada Vigilance Regional Office. Please notethat MAHs should submit reports to the MHPD Canada Vigilance Program, coordinateslisted in Appendix 4, and not the Canada Vigilance Regional Offices.


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4.1.3 Scientific Literature Reports

Every MAH is expected to screen the worldwide scientific literature on a regular basis by

accessing widely used systematic literature reviews or reference databases. It isrecommended that the frequency of the literature searches be at least every two weeks. Aqualified health care professional from the MAH should use their clinical judgement todetermine the appropriate frequency of literature searches based on the health productmarketed by the MAH. Cases of ARs from the scientific and medical literature,including relevant published abstracts from meetings and draft manuscripts, mightqualify for expedited reporting. A reporting form with relevant medical informationmust be provided for each identifiable patient. The publication reference(s) should begiven as the report source. Additionally, the MAH is expected to submit the article, and

is expected to translate the abstract into either English or French if the article is notpublished in one of the official languages. All MAH offices are encouraged to be awareof publications in their local journals and to bring them to the attention of the MAHsafety department as appropriate.

The regulatory reporting time clock starts as soon as the MAH has knowledge that thecase meets minimum criteria for reportability.

For foreign literature reports, all foreign serious unexpected ARs involving foreignproducts with the same combination of active ingredients irrespective of variations in theformulation, dosage form, strength, route of administration, or indication, that is also

marketed in Canada must be reported to the MHPD in accordance with theRegulations1,2,3 (see Section 2.1.2).

If the product source, brand, or trade name is not specified, the MAH should assume thatit was its product, although the report should indicate that the specific brand was notidentified.

If multiple products are mentioned in the article, a report should be submitted only by theMAH whose product is suspected. The suspect product(s) is/are those identified as suchby the articles author.

4.1.4 Stimulated Reports

Stimulated reports are those that may have been motivated, prompted or induced and canoccur in certain situations, such as notification by a Health Professional Communication


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(HPC), Health Canada-issued Public Advisory and/or Public Communication (PC),literature report, publication in the press, or questioning of health care professionals by

MAH representatives. These reports should be considered unsolicited in nature and mustbe reported to the MHPD in accordance with the Regulations1, 2, 3.

4.1.5 Reports via the Internet

MAHs should regularly screen websites under their management or responsibility forpotential AR case reports. MAHs are not expected to screen external websites for ARinformation. However, if a MAH becomes aware of an AR on a website that it does notmanage, the MAH should review the case and determine whether it should be reported.

MAHs should consider utilising their websites to facilitate AR data collection, e.g., by

providing AR forms for reporting or by providing appropriate contact details for directcommunication.

Cases from the Internet should be handled as unsolicited reports. For the determinationof reportability, the same minimum criteria (i.e., identifiable reporter, identifiable patient,suspect product and AR) should be applied as for cases provided via other ways. If theminimum reporting criteria are met and the report is considered relevant by a qualifiedhealth care professional from the MAH, the case is considered reportable and must beforwarded to the MHPD in accordance with the Regulations1,2,3.

4.1.6 Other Unsolicited Reports

If a MAH becomes aware of a case report from non-medical sources (e.g., the lay pressor other media), it should be handled as an unsolicited report. For the determination ofreportability, the same minimum criteria (i.e., identifiable reporter, identifiable patient,suspect product and AR) should apply as for other reports.

4.2 Solicited Reports

Solicited reports are defined by the ICH11 as those derived from organized data collectionsystems, which include clinical trials, registries, post-approval named patient use programs,

other patient support and disease management programs, surveys of patients or health careproviders, or information gathering on efficacy or patient compliance. Solicited reports do notoriginate with any safety issue or safety study, but invariably arise in the course of interactionwith patients for unrelated purposes. AR reports obtained from any of these sources should notbe considered unsolicited. Such reports are regarded as solicited in nature and one cannot infer


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implied causality, the convention for spontaneous reports. Solicited reports should also not beconfused with stimulated reports (see Section 4.1.4).

For the purposes of AR reporting, solicited reports should only be submitted if there is areasonable possibility that the health product caused the AR as determined by a qualified healthcare professional of the MAH. A reasonable possibility means that the relationship cannot beruled out. For example, using the World Health Organization criteria for causality applicable toAR reporting, any case reports that fall within the criteria of Certain, Probable, Possible, orUnlikely (see Appendix 6) must be reported to the MHPD. In any case where an underlyingillness or another health product may have contributed to the adverse event, the report shouldstill be considered an AR, as the causality cannot be ruled out.

4.2.1 Patient Support and Disease Management Programs

A number of solicited reports are generated through the increasing use of methods toencourage contact between consumers and the pharmaceutical company, such as throughmarketing programs as part of another patient support and disease management programused by pharmaceutical companies. Examples of these programs include, but are notlimited to, telephone services for patients to obtain direct advice, nurse-initiated calls formedicine compliance management, surveys collecting other patient data, andestablishment of large patient registries. These reports are clearly not generated in theusual spontaneous manner that is the premise upon which unsolicited reporting systemsare based; they are usually obtained incidentally to the main purpose of the program.

Reports generated through these programs are considered reportable in accordance withthe Regulations1,2,3.

4.2.2 Reports from Studies

For studies, this section of the guidance document refers to the post-market AR reportingrequirements for marketed health products, Division 1 (C.01.016 and C.01.017) andDivision 8 (C.08.007(h) and C.08.008(c)) of theFood and Drug Regulations and Section24 of theNatural Health Products Regulations.

MAHs are also subject to AR reporting for health products used in studies where theMAH is the sponsor of the study, in accordance with the requirements listed in Part C,Division 5 of theFood and Drug Regulations4, or Part 4 of theNatural Health ProductsRegulations. These requirements are not within the scope of this guidance document (seeAppendix 5 for contact information).


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4.2.2.1 Market Authorization Holder Sponsored Studies

Studies subject to post-market AR reporting requirements (e.g., phase IV studies)

should be monitored in a way that ensures that all serious domestic ARs, seriousunexpected foreign ARs and reports of domestic unusual failure in efficacy fornew drugs are reported to the MAH by the investigator(s) so that the MAH canprovide such reports to the MHPD within the 15-day period specified in theRegulations1, 2, 3.

Investigators should be provided with the definition of what constitutes a seriousAR for reporting purposes. In such cases, it is important to try to distinguishbetween reactions and events, not only for administrative purposes but also tominimize the instances of reporting adverse events that are clearly unrelated to

therapy. MAHs should help investigators understand their role in assessing thepossible relationship between an adverse event and the administration of a healthproduct during post-marketing studies.

Comparator and concomitant products used in these studies are within the scopeof this guidance document. It is the sponsors responsibility to decide whetheractive comparator and concomitant product adverse reactions should be reportedto the other MAH and/or directly to MHPD. Sponsors should report such eventsto either the MAH of the active control or to the MHPD.

4.2.2.2 Non-Market Authorization Holder Sponsored Studies

A MAH may receive study AR reports where its product was a comparatortreatment (and therefore used in accordance with approved labelling) or was aproduct the patient was taking concomitant to the study medication but wassuspected of causing an AR. The source of these reports may be another MAHwho is sponsoring the study, a private investigator or an academic centre. TheMAH must apply all principles outlined in this guidance document and theRegulations1, 2, 3 pertaining to reporting requirements, including determination ofseriousness, causality, and minimal criteria for submitting an AR report. The

MAH should not alter the causality assessment of the trial product(s) provided bythe trial sponsor and should include any narrative of the trial sponsor regardingcausality, if available. The MAH should assess causality on its own marketedhealth product(s).


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4.2.2.3 Post-Study Adverse Reactions

Although such information is not routinely sought or collected by the sponsor,

serious adverse reactions that occurred after the patient had completed a clinicalstudy (including any protocol-required post-treatment follow-up) will possibly bereported by an investigator to the sponsor. Such cases should be regarded forexpedited reporting purposes as though they were study reports. Therefore, acausality assessment is needed for a decision on whether or not expeditedreporting is required.

4.2.3 Blinded Study Reports(in Phase IV)

If the MAH receives a serious domestic AR report or a serious unexpected foreign AR

report from the investigator that is blinded to individual patient treatment, the code mustbe broken before submitting the report to the MHPD. Although it is advantageous toretain the blind for all patients prior to final study analysis, it is recommended that, whena serious AR occurs, the MAH seek a third party to break the blind only for that specificpatient, even if the investigator has not broken the blind. It is also recommended that,when possible and appropriate, the blind be maintained for individuals such as biometricspersonnel, who are responsible for analysis and interpretation of results at the conclusionof the study.

4.3 Regulatory Authority Sources

Individual serious unexpected AR reports originating from foreign regulatory authorities aresubject to expedited reporting to Health Canada by each MAH.

To avoid duplicate reporting, reports received by the MAH from the MHPD (e.g., AR reports,case reports published in the Canadian Adverse Reaction Newsletter (CARN), Canada VigilanceOn-line Database) are not required to be re-submitted to the MHPD by the MAH as they arealready contained within the Canada Vigilance Database. The MAH may, however, wish toinform the MHPD of their assigned identification number for reference. If the MAH is re-submitting the case with their identification number, the MAH should clearly indicate that thesource of the report is Health Canada and should include the Health Canada report ID number inthe narrative.

It is recommended that the MAH consult the Canada Vigilance On-line Database or request line-listing summaries to obtain reports that were sent directly to the Canada Vigilance Regional or


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National Offices (see Appendix 4 for contact information). Requests for line-listing summariesfrom the Canada Vigilance Database should be made in writing (letter, fax or e-mail) to MHPD.

Copies of AR reports must be requested through the Access to Information and Privacy Divisionof Health Canada and will require payment of the applicable fee.


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5 Summary Reports

In accordance with theFood and Drug Regulations1, the MAH must, on an annual basis and

whenever requested by the Director, conduct a concise, critical analysis of the adverse drugreactions (ADRs) and serious adverse drug reactions to a drug and prepare a summary report inrespect of the reports received during the previous twelve months or received during such periodof time as the Director may specify1. In accordance with theNatural Health ProductsRegulations3, the MAH must, on an annual basis, prepare and maintain a summary report thatcontains a concise and critical analysis of all domestic ARs to a natural health product, and allforeign serious unexpected ARs to a natural health product taken at the recommended dosereported during the previous twelve months.

The selected 12-month period for the annual summary report is specified by the MAH. The

summary report is to be maintained by the MAH on site or be easily accessible and, whenrequested, it is to be submitted to the MHPD within 30 calendar days. When Health Canadarequests the annual summary report, it is preferred that it be submitted in the Periodic SafetyUpdate Report (PSUR) format in accordance with the standards defined in the ICH E2C(R1)10

guideline.

In addition to complying with regulatory requirements to report safety and efficacy information,Health Canada expects that MAHs inform MHPD if the MAH concludes from the annualsummary report that there is a significant change in the risk-benefit profile of a product relatingto its safe use. Examples may include a significant change in the frequency or severity of a

known risk or the identification of a previously unknown risk.

5.1 Summary Report Format

The preferred format for annual summary reports prepared by MAHs is the PSUR format.PSURs based on multiples of six months with the summary bridging report are also appropriate.Further information regarding the summary bridging report integrating the information presentedin two or more PSURs to cover a specified period is available in the ICH E2C(R1)10 guideline.

MAHs may also use an annual summary report format as described below. This annualsummary report format does not contain information regarding the worldwide marketauthorization status and completed and planned studies, both of which are included in the PSURformat.

It is acceptable for the MAH to prepare a PSUR in ICH format according to the internationalPSUR schedule, be it every six months (with a summary bridging report), every year, three


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years, four years or five years while preparing an annual summary report for the years notcovered by the PSUR.

The information included in the annual summary report will vary depending on the adversereaction cases reported to the MAH and lack of significant new information should be mentionedfor each section.

Health Canada expects that the annual summary report will contain the following:

Introduction

Changes to the MAHs product safety information

Significant regulatory actions bearing on safety (domestic and foreign)

Line listing(s) and summary tabulations (see Section 5.2)

Critical Analysis:

A change in characteristics of expected reactions, e.g., severity, outcome, targetpopulation

Serious unexpected reactions, placing into perspective the cumulative reportssince marketing

Non-serious unexpected reactions An increased reporting frequency of expected reactions, including comments on

whether it is believed the data reflect a meaningful change in AR occurrence

Comparative analysis of reporting rates using patient exposure estimate (analysesmay be done in the context of amount of sales of the drug or by estimating thenumber of patient days of exposure)

The report should also explicitly address any new safety issue on the following(lack of significant new information should be mentioned for each):

drug interactions

experience with overdose, deliberate or accidental, and its treatment

drug abuse or misuse


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positive or negative experiences during pregnancy or lactation

experience in special patient groups (e.g., children, elderly, organ

impaired)

effects of long-term treatment

Other information (e.g., information related to effectiveness and late-breakinginformation)

Conclusion.

5.2 Line-listing(s) and Summary Tabulations

Health Canada expects that the following types of cases will be included in the line-listing andthat attempts will be made to avoid duplicate reporting of cases from the literature and regulatorysources:

for drugs, from unsolicited sources (see Section 4.1):

all domestic and foreign serious ARs

all domestic and foreign non-serious unexpected ARs

domestic cases of unusual failure in efficacy for new drugs

for drugs, from solicited sources where there is a reasonable possibility that the drugcaused the adverse reaction (see Section 4.2):


domestic cases of unusual failure in efficacy for new drugs

for drugs, from regulatory authority sources (see Section 4.3):


domestic cases of unusual failure in efficacy for new drugs for natural health products, from unsolicited sources and regulatory authority sources,

and from solicited sources where there is a reasonable possibility that the natural healthproduct caused the adverse reaction (see Section 4.2):


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all domestic ARs to a natural health product

all serious unexpected foreign ARs to a natural health product taken at the

recommended dose.

5.2.1 Presentation of the Line Listing

The line listing(s) should include each patient only once regardless of how many adversereaction terms are reported for the case. If there is more than one reaction, they shouldall be mentioned but the case should be listed under the most serious AR as judged by theMAH. It is possible that the same patient may experience different ARs on differentoccasions (e.g., weeks apart during a study). Such experiences would be treated asseparate reports. Under such circumstances, the same patient might then be included in a

line-listing more than once, and the line-listings should be cross-referenced whenpossible. Cases should be organized (tabulated) by body system (standard organ systemclassification scheme).

The following headings should usually be included in the line listing:

MAH case reference number

Country in which the case occurred

Source of report (e.g., clinical trial, literature, spontaneous, regulatory authority)

Age and gender

Daily dose of suspected health product (and, when relevant, dosage form or route)

Date of onset of the reaction

Dates of treatment

Description of reaction (MedDRA terminology is recommended)

Patient outcome (at case level) (e.g., resolved, fatal, improved, sequelae,

unknown). This field does not refer to the criteria used to define a serious AR.It should indicate the consequences of the reaction(s) for the patient, using theworst of the different outcomes for multiple reactions.


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Comments, if relevant (e.g., causality assessment if the MAH disagrees with thereporter; concomitant health products suspected to play a role in the reactions

directly or by interaction; indication treated with suspect health product(s);dechallenge/rechallenge results if available).

Depending on the health product or circumstances, it may be useful or practical to havemore than one line listing, such as for different dosage forms or indications, if suchdifferentiation facilitates presentation and interpretation of the data.

5.2.2 Summary Tabulations

An aggregate summary for each of the line listings should be presented. Thesetabulations ordinarily contain more terms than patients. It is useful to have separate

tabulations (or columns) for serious reactions and for non-serious reactions, for expectedand unexpected reactions; other breakdowns might also be appropriate (e.g., by source ofreport). When the number of cases is very small, or the information inadequate for anyof the tabulations, a narrative description rather than a formal table is considered suitable.


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6 Appendices

Appendix 1 Glossary: Definitions and Terminology

Adverse Event11(AE)

An adverse event is any untoward medical occurrence in a patient administered a medicinalproduct and which does not necessarily have to have a causal relationship with this treatment.An adverse event can therefore be any unfavourable and unintended sign (for example, anabnormal laboratory finding), symptom, or disease temporally associated with the use of amedicinal product, whether or not considered related to this medicinal product.

Adverse reaction (AR) for the purpose of this guidance document means a noxious andunintended response to a marketed health product covered by this document and includesadverse drug reaction as defined in theFood and Drug Regulations5 and adverse reaction asdefined in theNatural Health Products Regulations6.

Adverse Drug Reaction

Adverse drug reaction as defined in theFood and Drug Regulations5 is a noxious andunintended response to a drug, which occurs at doses normally used or tested for thediagnosis, treatment or prevention of a disease or the modification of an organic function.

Adverse Reaction

Adverse reaction as defined in theNatural Health Products Regulations6 is a noxious andunintended response to a natural health product that occurs at any dose used or tested forthe diagnosis, treatment or prevention of a disease or for modifying an organic function.

Brand Name(Food and Drug Regulations5)

With reference to a drug, the name, whether or not including the name of any manufacturer,corporation, partnership or individual, in English or French,

(a) that is assigned to the drug by its manufacturer,

(b) under which the drug is sold or advertised, and

(c) that is used to distinguish the drug.


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Brand Name(Natural Health Products Regulations6)

Means a name in English or French, whether or not it includes the name of a manufacturer,

corporation, partnership or individual

(a) that is used to distinguish the natural health product; and

(b) under which a natural health product is sold or advertised.

Canada Vigilance Program

Canada Vigilance is Health Canada's post-market surveillance program that collects and assessesadverse reaction reports to the following marketed health products: pharmaceuticals, biologics(including fractionated blood products, as well as therapeutic and diagnostic vaccines), natural

health products, radiopharmaceuticals and cells, tissues and organs. Canada Vigilance is aprogram of MedEffectTM Canada and is operated by the Marketed Health Products Directorate.

Common Name (Food and Drug Regulations5)

With reference to a drug, the name in English or French by which the drug is

(a) commonly known, and

(b) designated in scientific or technical journals, other than the publications referred to inSchedule B to the Act.

Common Name15 (Natural Health Products)

For any medicinal or non-medicinal ingredient contained in a natural health product, the nameby which it is commonly known and is designated in a scientific or technical reference.

Domestic AR

Adverse reaction occurring in Canada.

Drug

According to theFood and Drugs Act7, a drug includes any substance or mixture of substancesmanufactured, sold or represented for use in:

a. the diagnosis, treatment, mitigation or prevention of a disease, disorder orabnormal physical state, or its symptoms, in human beings or animals,


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b. restoring, correcting or modifying organic functions in human beings or animals,or

c. disinfection in premises in which food is manufactured, prepared or kept.

Expected AR

An AR whose nature (i.e., specificity or outcome), severity or frequency is consistent with theterm or description used in the product labelling should be considered expected.

Expedited AR Report

The following must be reported by the MAH within 15 calendar days of receiving information:

any serious domestic AR, any serious unexpected foreign AR, and

any domestic unusual failure in efficacy for a new drug.

Foreign AR

An adverse reaction occurring outside Canada to a pro

AE Reporting Guideline Canada 2009 Guidance-directrice Reporting-notification-Eng

Documents

Transcript of AE Reporting Guideline Canada 2009 Guidance-directrice Reporting-notification-Eng